144689-63-4

Basic information

• Product Name: Olmesartan Medoxomil
• Synonyms: (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl] 4-yl)methyl)-4-(;OMST;OlMesartan MedoxoMil SynoyM:4-(1-Hydroxy-1-Methylethyl)-2-propyl-1-[[2'-(1H-tetazol-5-yl)[1,1'-biphenyl]-4-yl]Methyl]-1H-iMidazole-5-carboxylic acid (5-Methyl-2-oxo-1,3-dioxol-4-yl)Methyl ester;1H-Imidazole-5-carboxylic acid, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester;Olmesartan medoxomil for system suitability;Olmesartan MedoxomiI;Olmesartan Medoxomi;(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hyd
• CAS NO: 144689-63-4
• Molecular Formula: C₂₉H₃₀N₆O₆
• Molecular Weight: 558.585
• EINECS: 1308068-626-2
• Product Categories: API;OMNICEF;Cardiovascular APIs;Active Pharmaceutical Ingredients;Aromatics;Bases & Related Reagents;Heterocycles;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Olmesartan;Inhibitor
• Mol File: 144689-63-4.mol

Chemical Properties

• Melting Point: 180°C
• Boiling Point: 804.2 °C at 760 mmHg
• Flash Point: 180°C
• Appearance: white to beige/
• Density: 1.38 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: soluble20mg/mL, clear
• PKA: 4.15±0.10(Predicted)
• CAS DataBase Reference: Olmesartan Medoxomil(CAS DataBase Reference)
• NIST Chemistry Reference: Olmesartan Medoxomil(144689-63-4)
• EPA Substance Registry System: Olmesartan Medoxomil(144689-63-4)

Safety Data

• RTECS: NI4014200
• Hazardous Substances Data: 144689-63-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Olmesartan medoxomil is used as an antihypertensive agent for the treatment of high blood pressure. It works by blocking the binding of angiotensin II to the AT1 receptors in vascular muscle, preventing angiotensin II-induced vasoconstriction and decreasing aldosterone production. This leads to a reduction in blood pressure and provides 24-hour blood pressure control with once-daily dosing.
Additionally, olmesartan medoxomil has been shown to be effective in reducing blood pressure more significantly than other angiotensin II receptor antagonists at their recommended doses, making it a preferred choice for patients with essential hypertension.
Olmesartan medoxomil is also used as a pro-drug that is de-esterified to the active metabolite, olmesartan. It has a dual method of elimination, with about 60% eliminated by the liver and the remainder by the kidney. This feature allows for alternative excretion pathways to compensate in cases of impaired renal or hepatic function. Furthermore, olmesartan is not metabolized by the cytochrome P450 enzyme system, resulting in a low potential for metabolic drug interactions, which is particularly important when treating patients on multiple drug regimens, such as the elderly.

Originator

Sanky (Japan)

Biochem/physiol Actions

Olmesartan medoxomil is a selective Angiotensin II Type I receptor blocker and antihypertensive drug. Olmesartan medoxomil is converted enzymatically to the active form olmesartan.

Clinical Use

Angiotensin-II receptor antagonist: Hypertension

Side effects

Dizziness or lightheadedness may occur as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Synthesis

Olmesartan Medoxomil can be synthesized in 8 steps from diaminomaleonitrile by successive reactions with trialkylorthopropanoate to access 2-propyl-imidazole-45dicarbonitrile, conversion of the two nitrile functions to the corresponding ethyl esters, followed by methylmagnesium bromide addition to give the corresponding 4-(1-hydroxyalkyl)imidazole derivative. The imidazole ring of olmesartan (18) was constructed with diaminomaleonitrile 155 and trimethylorthobutyrate (156) in CH3CN then xylene to give 157 in 96% yield. Acid hydrolysis of 157 in 6N HCl gave the dicarboxylic acid intermediate. After esterification of the diacid in ethanol in the presence of HCl, diester 158 was treated with MeMgCl to give 4-(1-hydroxyalkyl) imidazole 159 in 95% yield. Alkylation of 159 with biphenyl bromide 160 in the presence of potassium tbutoxide afforded 161 in 80% yield. Ester 161 was then hydrolyzed to free carboxylic acid 162 under basic conditions, and 162 was treated with chloride 163 in the presence of K2CO3 to give ester 164 in 88% yield from 161.Lastly, the trityl group was removed with 25% aqueous acetic acid to give olmesartan (18) in 81% yield.

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs. Antihypertensives: increased risk of hyperkalaemia hypotension and renal impairment with ACE-Is and aliskiren. Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity. Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics. ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect. Lithium: reduced excretion (possibility of enhanced lithium toxicity). Potassium salts: increased risk of hyperkalaemia. Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity.

Metabolism

Olmesartan medoxomil is an ester prodrug that is hydrolysed during absorption from the gastrointestinal tract to the active form olmesartan. It is excreted in the urine and the bile as olmesartan; about 35-50% of the absorbed dose is excreted in the urine and the remainder in the bile.

Synthetic route

trityl olmesartan medoxomil (144690-92-6) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With acetic acid In water at 25℃; for 1h;	100%
With hydrogenchloride In water; toluene at 20℃; for 2.5h;	98.6%
With TRILITE SCR-10 gel type In methanol for 6h; Product distribution / selectivity; Reflux;	94%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-({2'-[1-(2,4-dimethoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 25℃; for 6h; Time;	98%

trityl olmesartan medoxomil (144690-92-6) → triphenylmethyl alcohol (76-84-6) + olmesartan medoxomil (144689-63-4)

Conditions	Yield
Stage #1: trityl olmesartan medoxomil With sulfuric acid; water In acetone at 40℃; for 2 - 4h; Stage #2: With sodium hydrogencarbonate at 20℃; for 1h;	A n/a B 90%
With water In acetone for 14h; Product distribution / selectivity; Heating / reflux;	A n/a B 73%
With water In acetonitrile for 14h; Product distribution / selectivity; Heating / reflux;	A n/a B 71%

4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) + ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate (172875-59-1) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Stage #1: ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate With sodium hydroxide In N,N-dimethyl acetamide at 10 - 15℃; for 8h; Stage #2: 4-chloromethyl-5-methyl-1,3-dioxol-2-one With potassium carbonate In N,N-dimethyl acetamide at 0 - 65℃; for 10h;	90%

trityl olmesartan medoxomil → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With hydrogenchloride In water; toluene at 20℃; for 3h;	89%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-1-({2'-[1-(4-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-2-propyl-1H-imidazole-5-carboxylate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With trifluoroacetic acid at 25℃; for 72h; Temperature;	83%

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate (1020157-01-0) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With acetic acid at 80℃; for 2.5h;	81%
With sulfuric acid In water; acetone at 50 - 55℃; for 2h;	80%
With acetic acid In water at 55 - 60℃; for 2 - 3h; Product distribution / selectivity;
With hydrogenchloride In methanol; dichloromethane at 0 - 5℃; for 1 - 2h;

ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-({2'-[1-(triphenylmethyl)-1H-1,2,3,4-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl}methyl)-1H-imidazole-5-carboxylate (144690-33-5) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
	71%
Multi-step reaction with 2 steps 1.1: diisopropylamine; sodium hydroxide / toluene; ISOPROPYLAMIDE / 4 h / 25 - 45 °C 1.2: 8 h / 40 - 70 °C 1.3: 25 - 35 °C / pH ~ 6 - 7 2.1: hydrogenchloride; water / methanol / 1 h / 0 - 35 °C 2.2: 25 - 35 °C / pH ~ 3 - 4 View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate; water / acetone / 16 h / 20 °C 2.1: potassium carbonate; potassium iodide / acetone / 3 h / 50 - 55 °C 3.1: hydrogenchloride; water / toluene / 3 h / 20 °C 3.2: 15 - 20 °C / pH 4.5 - 5.5 View Scheme

2-propyl-1H-imidazole-4,5-dicarboxylic acid (58954-23-7) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: 86 percent / HCl / Ambient temperature 2: 95 percent / diethyl ether; CH2Cl2 / 1 h / 10 - 15 °C 3: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 4: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 5: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 6: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole (133051-88-4) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 2: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 3: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 4: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme
Multi-step reaction with 4 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C 2: potassium hydroxide; water / N,N-dimethyl-formamide / 22 h / 54 - 56 °C 3: potassium iodide; potassium carbonate / 20 °C 4: sulfuric acid / water; acetone / 2 h / 50 - 55 °C View Scheme

2-propyl-1H-imidazole-4, 5-diethyl azodicarboxylate (144689-94-1) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 95 percent / diethyl ether; CH2Cl2 / 1 h / 10 - 15 °C 2: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 3: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 4: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 5: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate (144689-93-0) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 2: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 3: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 4: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene / 0.75 h / 45 - 50 °C 1.2: 10 h / 60 - 70 °C 2.1: diisopropylamine; sodium hydroxide / toluene; ISOPROPYLAMIDE / 4 h / 25 - 45 °C 2.2: 8 h / 40 - 70 °C 2.3: 25 - 35 °C / pH ~ 6 - 7 3.1: hydrogenchloride; water / methanol / 1 h / 0 - 35 °C 3.2: 25 - 35 °C / pH ~ 3 - 4 View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / tetrabutylammomium bromide / acetone / 15 h / 50 - 55 °C 2.1: potassium carbonate; water / acetone / 16 h / 20 °C 3.1: potassium carbonate; potassium iodide / acetone / 3 h / 50 - 55 °C 4.1: hydrogenchloride; water / toluene / 3 h / 20 °C 4.2: 15 - 20 °C / pH 4.5 - 5.5 View Scheme

ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate (172875-59-1) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 2: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 3: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1: potassium hydroxide; water / N,N-dimethyl-formamide / 22 h / 54 - 56 °C 2: potassium iodide; potassium carbonate / 20 °C 3: sulfuric acid / water; acetone / 2 h / 50 - 55 °C View Scheme

4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid lithium salt → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 2: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

2-propylimidazole-4,5-dicarbonitrile (51802-42-7) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 7 steps 1: 80 percent / 6N aq. HCl / 8 h / Heating 2: 86 percent / HCl / Ambient temperature 3: 95 percent / diethyl ether; CH2Cl2 / 1 h / 10 - 15 °C 4: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 5: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 6: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 7: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

olmesartan medoxomil hydrobromide → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With sodium hydrogencarbonate In water; acetone at 0 - 20℃; for 2 - 3h; pH=5.6; Product distribution / selectivity;

trityl olmesartan medoxomil (144690-92-6) + 4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Stage #1: trityl olmesartan medoxomil With hydrogenchloride; ethanol; water at 24 - 26℃; for 3h; Stage #2: 4-chloromethyl-5-methyl-1,3-dioxol-2-one With sodium hydroxide In ethanol; water for 0.25h; pH=5;

N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole (124750-51-2) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene / 0.75 h / 45 - 50 °C 1.2: 10 h / 60 - 70 °C 2.1: diisopropylamine; sodium hydroxide / toluene; ISOPROPYLAMIDE / 4 h / 25 - 45 °C 2.2: 8 h / 40 - 70 °C 2.3: 25 - 35 °C / pH ~ 6 - 7 3.1: hydrogenchloride; water / methanol / 1 h / 0 - 35 °C 3.2: 25 - 35 °C / pH ~ 3 - 4 View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / tetrabutylammomium bromide / acetone / 15 h / 50 - 55 °C 2.1: potassium carbonate; water / acetone / 16 h / 20 °C 3.1: potassium carbonate; potassium iodide / acetone / 3 h / 50 - 55 °C 4.1: hydrogenchloride; water / toluene / 3 h / 20 °C 4.2: 15 - 20 °C / pH 4.5 - 5.5 View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / dimethyl sulfoxide; acetone / 2.5 h / 0 - 5 °C / Reflux 2.1: sodium hydroxide / dimethyl sulfoxide; tetrahydrofuran / 2 h / 17 - 60 °C 2.2: 2.5 h / 70 °C 3.1: hydrogenchloride / acetonitrile; water / 2 h / 5 °C 3.2: pH 5.7 View Scheme

potassium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (936114-12-4) + 4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl acetamide / 3 h / 0 - 45 °C 2: hydrogenchloride; water / methanol; ethyl acetate / 2 h / 20 °C View Scheme

benzoyl chloride (98-88-4) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: triethylamine / tetrahydrofuran / 3 h / 2 - 35 °C 2.1: phosphorus pentachloride / dichloromethane / 3 h / -15 - 21 °C 2.2: 4.5 h / -8 - 30 °C 3.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 4.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 5.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 6.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 7.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 8.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 9.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 9.2: 12 h / 45 - 50 °C 10.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme

N-benzylbenzamide (1485-70-7) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: phosphorus pentachloride / dichloromethane / 3 h / -15 - 21 °C 1.2: 4.5 h / -8 - 30 °C 2.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 3.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 4.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 5.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 6.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 7.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 8.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 8.2: 12 h / 45 - 50 °C 9.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme

1-benzyl-5-phenyl-1H-tetrazole (28386-90-5) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 2.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 3.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 4.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 5.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 6.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 7.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 7.2: 12 h / 45 - 50 °C 8.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 138 - 140 °C / Inert atmosphere 2: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme
Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 12 h / 138 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / ethyl acetate / 6 h / Reflux 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme

4-bromobenzyl benzoate (38612-13-4) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 2.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 3.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 4.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 5.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 6.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 7.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 7.2: 12 h / 45 - 50 °C 8.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 138 - 140 °C / Inert atmosphere 2: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme

{2'-(1-benzyl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl}methyl benzoate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 2.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 3.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 4.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 5.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 6.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 6.2: 12 h / 45 - 50 °C 7.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 7 steps 1: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 2: potassium carbonate / acetonitrile / 18 h / 84 °C 3: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 4: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 5: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 6: potassium iodide / butanone / 20 h / 50 °C 7: acetic acid / water / 1 h / 25 °C View Scheme

1-benzyl-5-[4'-(bromomethyl)biphenyl-2-yl]-1H-tetrazole → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 2.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 3.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 4.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 5.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 5.2: 12 h / 45 - 50 °C 6.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1: potassium carbonate / acetonitrile / 18 h / 84 °C 2: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 3: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 4: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 5: potassium iodide / butanone / 20 h / 50 °C 6: acetic acid / water / 1 h / 25 °C View Scheme

ethyl 4-(1-hydroxy-1-methylethyl)-1-({2′-[1-(phenylmethyl)-1H-tetrazol-5-yl][1,1′-biphenyl]-4-yl}methyl)-2-propyl-1H-imidazole-5-carboxylate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 2.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 3.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 4.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 4.2: 12 h / 45 - 50 °C 5.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 2: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 3: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 4: potassium iodide / butanone / 20 h / 50 °C 5: acetic acid / water / 1 h / 25 °C View Scheme

ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (144689-23-6) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 2.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 3.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 3.2: 12 h / 45 - 50 °C 4.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 2: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 3: potassium iodide / butanone / 20 h / 50 °C 4: acetic acid / water / 1 h / 25 °C View Scheme

potassium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (936114-12-4) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 1.2: 12 h / 45 - 50 °C 2.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1: potassium iodide / butanone / 20 h / 50 °C 2: acetic acid / water / 1 h / 25 °C View Scheme

para-bromotoluene (106-38-7) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 12 h / 138 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / ethyl acetate / 6 h / Reflux 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme

olmesartan medoxomil (144689-63-4) → 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylic acid dipotassium salt

Conditions	Yield
With water; sodium hydroxide In methanol at 20℃; for 24h;	96%

olmesartan medoxomil (144689-63-4) → olmesartan

Conditions	Yield
With sodium hydroxide In methanol; water at 20 - 30℃; for 20h;	90%
In water for 24h; Reflux;	88%
With water for 24h; Reflux;	88%
With Bis(p-nitrophenyl) phosphate In dimethyl sulfoxide; acetonitrile at 37℃; for 0.0333333h; pH=7.4; Reagent/catalyst; Enzymatic reaction;

methanol (67-56-1) + olmesartan medoxomil (144689-63-4) → 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid (1039762-40-7)

Conditions	Yield
for 24h; Reflux;	85%
for 24h; Reflux;	85%
for 24h; Reflux;	85%

p-methoxybenzyl chloride (824-94-2) + olmesartan medoxomil (144689-63-4) → (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-1-({2'-[1-(4-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-2-propyl-1H-imidazole-5-carboxylate

Conditions	Yield
With tetrabutylammomium bromide; sodium carbonate In chloroform; water at 10 - 55℃; for 11h;	20.6%

olmesartan medoxomil (144689-63-4) → olmesartan medoxomil hemihydrate

Conditions	Yield
With water In dimethyl sulfoxide at 20℃;

olmesartan medoxomil (144689-63-4) → (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl1-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)-4-(prop-1-en-2-yl)-2-propyl-1H-imidazole-5-carboxylate (879562-26-2)

Conditions	Yield
Stage #1: olmesartan medoxomil With sulfuric acid In ISOPROPYLAMIDE at 100℃; for 2.5h; Inert atmosphere; Stage #2: With sodium hydroxide In dichloromethane; ISOPROPYLAMIDE; water at 40℃; pH=4.2;

olmesartan medoxomil (144689-63-4) → 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid (1039762-40-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: water / 24 h / Reflux 2: 24 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: water / 24 h / Reflux 2: 24 h / Reflux View Scheme

olmesartan medoxomil (144689-63-4) → 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid (1039762-40-7) + olmesartan methyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: water / 24 h / Reflux 2: triphenylphosphine; di-isopropyl azodicarboxylate / dichloromethane / 5 h / 20 °C View Scheme

Upstream product

• 1020157-01-0 (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate 
• 58954-23-7 2-propyl-1H-imidazole-4,5-dicarboxylic acid 
• 144689-94-1 diethyl 2-(n-propyl)-1H-imidazole-4,5-dicarboxylate 
• 144690-92-6 trityl olmesartan medoxomil 
• 80841-78-7 4-chloromethyl-5-methyl-1,3-dioxol-2-one 
• 124750-51-2 N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole 
• 936114-12-4 potassium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate 
• 98-88-4 benzoyl chloride 
• 1485-70-7 N-benzylbenzamide 
• 28386-90-5 5-benzyl-1-phenyl-1H-tetrazole 
• 38612-13-4 4-bromobenzyl benzoate 
• 144689-23-6 ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 168265-56-3 1-benzyl-5-(4'-methyl-[1,1'-biphenyl]-2-yl)-1H-tetrazole 
• 879097-59-3 sodium 4-(2-hydroxypropan-2-yl)-2-propyl-1-({2'-[1-(triphenylmethyl)-1H-1,2,3,4-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl}methyl)-1H-imidazole-5-carboxylate 

Downstream Products

• 1039762-40-7 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid 
• 752179-89-8 1-((2'-(2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid 
• 879562-26-2 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl1-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)-4-(prop-1-en-2-yl)-2-propyl-1H-imidazole-5-carboxylate 
• 172875-98-8 1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(prop-1-en-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid 

Relevant articles and documents

Understanding and Controlling the Formation of an N-Alkyl Impurity in Olmesartan Medoxomil: A Derivative via Michael-Type Addition between Tetrazole and Mesityl Oxide in Situ Generated from Acetone

An unknown impurity was detected in olmesartan medoxomil active pharmaceutical ingredient (API), which was determined as 2-methyl-4-oxopentan-2-yl-protected olmesartan medoxomil by NMR and mass spectrometry (MS). The formation mechanism of this impurity was investigated. In summary, the tetrazole of the final product was condensed with the potential genotoxic compound mesityl oxide generated from acetone self-condensation in acidic conditions to form the N-Alkyl impurity. Further quality control of the reaction was investigated using statistical methods (design of experiment, DoE) via a definitive screening design. The key factors of the reaction were determined to control the process parameters. Three batches of validation experiments showed that the generation of the N-Alkyl impurity was suppressed (0.1%) and the residual mesityl oxide was not detected (2.5 ppm).

2,4-Dimethoxybenzyl Group for the Protection of Tetrazole: An Efficient Synthesis of Olmesartan Medoxomil through C-H Arylation

The 2,4-dimethoxybenzyl (DMB) group was found to be effective for protecting tetrazoles. The DMB group is inert to various conditions, including those for ruthenium-catalyzed C-H arylation, but is readily cleaved under mild conditions. The use of a DMB protecting group permitted a synthesis of highly functionalized olmesartan medoxomil in a few steps.

Preparation method of high purity olmesartan medoxomi I

The invention relates to a preparation method of high purity olmesartan medoxomi I. The preparation method comprises following steps: 1,5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (A) and ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (B) are taken as raw materials to prepare an olmesartan medoxomi I intermediate 1 (C) through condensation reaction; theolmesartan medoxomi I intermediate 1 (C) is subjected to hydrolysis in the presence of sodium hydroxide so as to obtain a compound (D); without separation, the compound (D) and raw material 4-Cloromethyl-5-methyl-1,3-dioxol-2-one (E) are directly subjected to condensation reaction so as to obtain an olmesartan medoxomi I intermediate 2 (F); and the olmesartan medoxomi I intermediate 2 (F) is subjected to deprotection in a 75% acetic acid aqueous solution so as to obtain olmesartan medoxomi I crude product, and acetone is adopted for recrystallization so as to obtain high purity olmesartan medoxomi I (G). The reaction conditions are mild; side products are few; the finished product purity is high; the preparation method is safe, is friendly to the environment, and is suitable for industrialized production; residual solvent is less; and quality standards are achieved.

A trityl protecting group by removing method of preparing losartan medicine

The invention discloses a method for preparation of a Sartan drug by removal of a triphenylmethyl protective group. The method includes: under the catalysis of an insoluble weak acid, subjecting a Sartan prodrug and methanol to deprotection reaction, and after complete reaction, conducting aftertreatment to obtain the Sartan drug. The method has the characteristics of low cost, few side product, high quality product, and simple aftertreatment. At the same time, montmorillonite can be taken as insoluble weak acid, and the cost is low, thus being convenient for industrial production.

A olmesartan medoxomil and its preparation method (by machine translation)

The invention discloses a olmesartan medoxomil and its preparation method, the present invention discloses a olmesartan medoxomil, its chemical structure is: The present invention novel method for preparation method, comprises the following steps: (1) preparing AMST - 3 C45 H44 N6 O3 ; (2) preparing C43 H39 N6 NaO3 AMST - 4; (3) preparing C48 H44 N6 O6 AMST - 6; (4) preparing olmesartan sha tanzhi thick; (5) to make the C29 H30 N6 O6 Olmesartan medoxomil. The invention separation effect is good, relatively low viscosity system, split-phase required time is short, the time is saved but also reduces energy consumption. Filtering and separating the high recovery rate, the product quality is high, the running cost is low; process without the need to add chemical, solvent solvent, not into the secondary pollution material; equipment and automatic operation, good stability, easy to realize industrial demand. (by machine translation)

Production of [orumesarutanmedokisomiru[orumesarutanmedokisomiru]

PROBLEM TO BE SOLVED: To provide a method for easily producing a crystal of a high-purity (5-methyl-2-oxo-1,3-dioxolene-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazole-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate in which the content of low polar impurities derived from olmesartan is reduced.SOLUTION: There is provided a method of carrying out a deprotection reaction of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trimethyltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid(5-methyl-2-oxo-1,3-dioxolene-4-yl)methylester in an acid aqueous solution having a pKa of 2.5 to 6.0 at a temperature of 30 to 45°C.

Preparation method of olmesartan medoxomil

The invention discloses a preparation method of olmesartan medoxomil. The preparation method comprises the following steps of using 4-bromobenzaldehyde as a starting raw material, performing Suzuki coupling reaction with 2-(2'-triphenylmethyl tetrazole-5-yl)borophenylic acid (III), and reducing by NaBH4 (sodium borohydride), so as to obtain an olmesartan medoxomil intermediate of N-triphenylmethyl-5-(4'-hydroxymethyl biphenyl-2-yl)tetrazole (IV); directly reacting the intermediate (IV) and 2-propyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid ethyl ester, so as to obtain a compound VI; performing hydrolysis, esterification and deprotection, so as to obtain the olmesartan medoxomil. Compared with the prior art, the preparation method has the advantages that the obtaining of raw materials is easy, the amount of byproducts is fewer, the reaction line is shortened, the reaction condition is mild, the operation is simple, the total yield of product is improved, and the preparation method is suitable for industrialized production.

Method for preparing olmesartan medoxomil

The invention provides a method for preparing olmesartan medoxomil and belongs to the field of medicine synthesis. The method comprises the steps that imidazole monoester and 5-(4'-Bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (BBTT) are used as starting materials and subjected to condensation, hydrolysis and acidification through a one-pot method in an acetone system to obtain 4-(1-hydroxyl-1-methylethyl)-2-propyl-{4-[2-(triphenylmethyl tetrazole-5-base) phenyl] phenyl} methylimidazole-5-carboxylic acid; the obtained product is then esterified with 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone, wherein the purity of the esterified product through purification is larger than or equal to 99.5%; the esterified product is subjected to deprotection under the action of a 22.5% sulfuric acid solution to obtain highly purified olmesartan medoxomil. Condensation and esterification are performed through the one-pot method, so that the operation procedure is simplified, control is facilitated, the key intermediate esterified product is purified and then subjected to deprotection in the reaction, the olmesartan medoxomil with purity larger than or equal to 99.5% can be obtained, the total yield can reach 60%-75%, the raw materials are easy to obtain, cost is low, and the method is applicable to industrial production.

Preparation method of key intermediate of olmesartan medoxomil and olmesartan medoxomil

The invention relates to a preparation and refinement method of a key intermediate of olmesartan medoxomil and the olmesartan medoxomil, and belongs to the technical field of medicine. The structural formula of the olmesartan medoxomil is shown as a formula I (Please see the specification).

A process for the preparation of olmesartan

The invention discloses a preparation method of Olmesartan Medoxomil. The method is used for synthesizing an important intermediate 4-[2-(2-triphenylmethyl tetrazole-5-yl) phenyl] benzyl bromide (a compound III) so as to prepare the compound Olmesartan Medoxomil. The method is high in yield, easy to separate and purify, simple to operate and suitable for industrial production.